Affective disorder is a common, seriously disabling mental illness. The proposed relationship between susceptibility to effective disorder and genes in the HLA region of chromosome 6 (1) has been contested (17,18). We anticipate, based on an analysis of the available data, that a properly designed study, testing the right hypotheses, will demonstrate a major role of genes on chromosome 6 in determining susceptibility to affective disorder. We propose to study 10 - 15 nuclear families, each containing two or more first degree relatives with affective disorder. Psychiatric diagnoses, using RDC criteria, will be based on results obtained from the NIMH Diagnostic Instrument Schedule, administered by personnel experienced with this instrument and with psychiatric family studies. The data presented in the initial proposal were obtained from 38 nuclear families in 21 kindreds (1). The results in the proposed study (total of 30 - 35 nuclear families studied over 3 years) will be tested against the published hypotheses concerning the distribution of HLA haplotypes among affected and unaffected individuals in families having various constellations of affected and unaffected members. The complexity of the relationship between HLA and affective disorder is highlighted by the evidence, developed during the 01 grant period, of an association between affective disorder and both HLA-DR5 and DR7. The hypothesis concerning these associations was formulated after testing 34 unrelated individuals with unipolar depression and 34 ethnically-matched controls for HLA-DR antigens. The hypothesis was tested in 10 multiplex families having at least one member with DR5 or DR7: 22/25 affected family members had DR5 or DR7 as compared with 15/30 unaffected family members (p less than O.OO5). This association will be further investigated in the proposed study. An established relationship between HLA and depressive disorder would provide clues to the pathogenesis of depression and might aid in clarifying its relationship to other disorders found in increased frequency in the relatives of patients with primary depression.